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X-ray crystallography reveals structure of precursor to blood-clotting protein

Date:
November 6, 2010
Source:
Saint Louis University
Summary:
Using state-of-the-art robotic and x-ray crystallographic equipment, researchers have revealed for the first time the molecular structure of the zymogen, or inactive, form of a blood-clotting enzyme.

Thrombin structure.
Credit: Image courtesy of Saint Louis University

Using state-of-the-art robotic and x-ray crystallographic equipment, researchers at Saint Louis University have revealed for the first time the molecular structure of the zymogen, or inactive, form of a blood-clotting enzyme.

In an article published in Proceedings of the National Academy of Sciences, Enrico Di Cera, M.D., chair of the department of biochemistry and molecular biology at Saint Louis University School of Medicine and lead researcher of the study, said the NIH-funded research offers important information about the protein.

"This research is very basic and very important," said Di Cera. "It provides a missing link between the inactive zymogen form of thrombin and the mature enzyme generated upon vascular injury."

Before thrombin becomes active, it circulates throughout the blood in the inactive zymogen form. When the active enzyme is needed, for example after a vascular injury, the coagulation cascade is initiated and the zymogen is converted into an active enzyme that causes blood to clot.

Blood clotting performs the important function of stopping blood loss after an injury. However, when triggered in the wrong conditions, clotting can lead to debilitating or fatal conditions like heart attack, stroke and deep vein thrombosis.

In previous laboratory research, Di Cera re-engineered thrombin to act as an anticoagulant, stopping blood from clotting and opening the door to the development of new therapeutic strategies for the treatment of thrombosis, the presence of blood clots in blood vessels, which is responsible for nearly a third of all deaths in the U.S.

While researchers have an understanding of the structure of active thrombin, very little was known about its zymogen form. In order to learn more, researchers used x-ray crystallography to gather data about the molecular structure of the protein.

The process involves growing a crystal of the protein, shooting x-ray beams through the crystal and analyzing the diffraction pattern generated on a detector plate in order to detail the three-dimensional structure of the protein.

The structure of the zymogen form of thrombin provides crucial details about the activation mechanism that sheds light on the way the mature enzyme works. Future research can capitalize on these new findings to define better strategies for therapeutic intervention.

"Until now, we've known nothing about the zymogen form of thrombin or any blood-clotting enzyme," said Di Cera. "All the structural information has been limited to the active form.

"We now know that the zymogen form of thrombin is very different from the mature enzyme, in ways that open new opportunities for therapeutic intervention."

Established in 1836, Saint Louis University School of Medicine has the distinction of awarding the first medical degree west of the Mississippi River. The school educates physicians and biomedical scientists, conducts medical research, and provides health care on a local, national and international level. Research at the school seeks new cures and treatments in five key areas: cancer, liver disease, heart/lung disease, aging and brain disease, and infectious disease.


Story Source:

The above story is based on materials provided by Saint Louis University. Note: Materials may be edited for content and length.


Journal Reference:

  1. Zhiwei Chen, Leslie A. Pelc, Enrico Di Cera. Crystal structure of prethrombin-1. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1010262107

Cite This Page:

Saint Louis University. "X-ray crystallography reveals structure of precursor to blood-clotting protein." ScienceDaily. ScienceDaily, 6 November 2010. <www.sciencedaily.com/releases/2010/11/101102091104.htm>.
Saint Louis University. (2010, November 6). X-ray crystallography reveals structure of precursor to blood-clotting protein. ScienceDaily. Retrieved July 25, 2014 from www.sciencedaily.com/releases/2010/11/101102091104.htm
Saint Louis University. "X-ray crystallography reveals structure of precursor to blood-clotting protein." ScienceDaily. www.sciencedaily.com/releases/2010/11/101102091104.htm (accessed July 25, 2014).

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